This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Natural Killer T (NKT) lymphocytes are a unique subset of T lymphocytes that have an invariant TCR Valpha chain and recognize ligands presented by the nonpolymorphic CD1d molecule. Functionally, CD1d-reactive NKT cells can secrete large amounts of both Th-1 and Th-2 type cytokines, including IL-10, and are early effectors of the innate immune system. NKT cells have been shown to protect against autoimmunity and immunopathology in diabetes-prone NOD mice and prevent experimental autoimmune encepholomyelitis in mice. In humans, invariant NKT cells are mainly CD4-positive and CD4/8 double negative T lymphocytes and are lost early in HIV infection. By virtue of the diverse cytokines that they secrete, NKT cells may play a role in modulating immune activation in HIV and SIV infection. Sooty mangabeys are a natural host of SIV that do not progress to AIDS. A key differentiating feature of SIV infection in its natural host is the absence of aberrant immune activation. In this project we are investigating whether NKT cells are responsible for the lack of aberrant immune activation in naturally SIV-infected sooty mangabeys. Flow cytometric evaluation of peripheral blood has revealed detectable frequencies of circulating Valpha24positive CDld-tetramer positive NKT lymphocytes in sooty mangabeys but not rhesus macaques. Functionally, mangabey NKT cells secrete IFN-gamma, IL-2, IL-4, IL-10, and IL-13 in a cD1d-restricted manner, and are also capable of degranulation suggesting cytolytic function. Cross-sectional analysis of NKT cells in 60 SIV-negative and 46 SIV-infected sooty mangabey is in progress.